University of Texas-Houston (UTH) Medical School and collaborating clinical and basic investigators at the UTH-M.D. Anderson Cancer Canter and the UTH-School of Public Health (Human Genetics Canter) propose the establishment of a Specialized Center of Research (SCOR) in Scleroderma (systemic sclerosis or SSc) or UTH-COR-SSc. The Director of UTH-SCOR- SSc will be Frank C. Arnett, MD and the Co-Directors Benoit de Crombrugghe, M.D. (for basic research) and John D. Reveille, MD. (for clinical research). SSc is an uncommon but devastating human disease with high mortality and no effective treatment characterized by diffuse cutaneous and visceral fibrosis. The pathogenesis of SSc is unknown, however, there is evidence for both genetic and environmental influences. Thus, the central theme of UTH-SCOR-SSc is the use of molecular approaches to understand pathogenetic, mechanisms, especially genetic factors, and the predictors of outcomes in SSc. Four interacting clinical and basic research projects and two cores are proposed, as follows: 1) a human genome-wide search for SSc-associated genes using microsatellite mapping and beginning with candidate genes in a unique Native American population with high disease prevalence; 2) basic investigations of type I collagen gene regulation by transforming growth factor (TGF) beta and other factors in transgenic mice and the tight skin (tsk) 1 murine model of fibrosis (and SSc); 3) characterization of pulmonary macrophage phenotypes and their roles in promoting fibrosis of the lung in early SSc patients and the potential usefulness of early cytotoxic therapy (based on macrophage phenotype) in ameliorating lung damage; 4) a large study of potential demographic, clinical, autoantibody and genetic predictors of disease outcomes in three ethnic groups (Caucasians, African-Americans and Mexican- Americans); 5) a Tissue Culture Core to process and store lymphoblastoid cell lines (for genomic DNA), fibroblasts and pulmonary macrophages from SSc patients for the projects proposed; and 6) an Administrative and Biostatistical Core for administering UTH-SCOR-SSc and providing data management, and biostatistical analysis for the projects proposed. The studies proposed here will provide better understanding of both the fundamental pathogenetic mechanisms and potentially useful clinical predictors of outcome in SSc which will lead to more directed therapies and/or disease prevention.